176P - Patient race is a determinant of the impact of Y chromosome loss on survival

Background

Loss of Y chromosome (LOY) in tumors is correlated with poor overall survival (OS), due to immune evasion in certain tumor types. While studies have linked LOY with smoking and age, it remains unknown if the impact of LOY on OS is dependent on patient race and if so, whether this is associated with differences in the tumor immune microenvironment (TME). This study aimed to evaluate the impact of LOY tumors on tumor microenvironment across different racial groups and its subsequent effect on survival outcome.

Methods

4127 male TCGA patients with race and OS data were used. Bulk RNA-seq LOY signature was created with ssGSEA to classify patients with LOY (LOY_BR) and wild-type Y chromosome (WTY_BR). For robustness, a DNA-based LOY signature (LOY/WT) was also used. These signatures were used to stratify OS using Kaplan-Meier analysis. Moreover, genomic instability, hallmark G2M checkpoint pathway scores were evaluated with ssGSEA and a differential analysis of immune checkpoint genes among racial groups was carried out. The Wilcoxon-rank sum test was used for statistics.

Results

White and Asian with LOY tumors experienced worse OS (White, P < 0.001; Asian, P = 0.003) than those with WTY tumors. Furthermore, the separation between LOY and WTY appears more pronounced in Asian (HR=1.93) compared to White (HR=1.31). Contrary to White and Black, Asians with LOY tumors showed reduced expressions of repair mechanisms of DNA, nucleotide excision, and base excision. Furthermore, tumor LOY impact on the G2M checkpoint cell cycle pathway was most notable in Asian (log2FC=0.56, p<0.001), followed by those of White (log2FC=0.34, p<0.001). Asian with LOY tumors had elevated expression of CTLA4, LAG3, HAVCR2 and PDCD1, indicating T-cell exhaustion (p<0.001), while White and Black only had elevation in 3 and 1 of these respectively. Overall RNA methods showed consistency compared to DNA methods demonstrating robustness.

Conclusions

We are the first to report that tumor LOY has a different impact as a function of patient race. Asian with LOY tumors showed pronounced genomic instability, cell cycle progression, likely contributing more aggressive tumors. Elevated expression of immune checkpoint molecules in LOY tumors in Asian may indicate a better response to immune checkpoint blockade (ICB).

Editorial acknowledgement

Clinical trial identification

Legal entity responsible for the study

The authors.

Funding

National Institutes of Health (NIH).

Disclosure

All authors have declared no conflicts of interest.